Neurofibrillary tangle formation as a protective response to oxidative stress in Alzheimer's disease

Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau are major hallmarks of Alzheimer's disease (AD). Because the formation of NFTs reflects a hierarchy of neuronal vulnerability and their distribution parallels disease severity, NFTs formation has been suspected to play a major role in the disease pathogenesis. However, theoretically, either pathogenic alterations of the disease or protective responses to the disease pathogenesis can be observed according to the hierarchy of the vulnerability. Indeed, the majority of neuronal death in AD likely occurs without the process of NFT formation and neurons may live for decades with NFTs. More important, there is a growing body of evidence suggesting that tau phosphorylation and conformational changes are inducible by oxidative insults and the neuronal oxidative damage in AD is actually alleviated through the process of NFT formation. In line with recent evidence that neuronal cellular inclusions represent a protective function, rather than being initiators or accelerators of disease pathogenesis, we suspect that the NFTs function as a cytoprotective response especially a primary line of antioxidant defense. An involvement of tau phosphorylation in the insulin-like signaling pathway affecting organism longevity implicates an essential link between NFT formation and an adaptation under oxidative stress in age-associated neurodegeneration.